Background The extent of differences between genetic risks associated with various asthma subtypes is still unknown. To better understand the heterogeneity of asthma, we employed an unsupervised method to identify genetic variants specifically associated with asthma subtypes. Our goal was to gain insight into the genetic basis of asthma. Methods In this study, we utilized the UK Biobank dataset to select asthma patients (All asthma, n = 50,517) and controls (n = 283,410). We excluded 14,431 individuals who had no information on predicted values of forced expiratory volume in one second percent (FEV1%) and onset age, resulting in a final total of 36,086 asthma cases. We conducted k‐means clustering based on asthma onset age and predicted FEV1% using these samples (n = 36,086). Cluster‐specific genome‐wide association studies were then performed, and heritability was estimated via linkage disequilibrium score regression. To further investigate the pathophysiology, we conducted eQTL analysis with GTEx and gene‐set enrichment analysis with FUMA. Results Clustering resulted in four distinct clusters: early onset asthmanormalLF (early onset with normal lung function, n = 8172), early onset asthmareducedLF (early onset with reduced lung function, n = 8925), late‐onset asthmanormalLF (late‐onset with normal lung function, n = 12,481), and late‐onset asthmareducedLF (late‐onset with reduced lung function, n = 6508). Our GWASs in four clusters and in All asthma sample identified 5 novel loci, 14 novel signals, and 51 cluster‐specific signals. Among clusters, early onset asthmanormalLF and late‐onset asthmareducedLF were the least correlated (rg = 0.37). Early onset asthmareducedLF showed the highest heritability explained by common variants (h2 = 0.212) and was associated with the largest number of variants (71 single nucleotide polymorphisms). Further, the pathway analysis conducted through eQTL and gene‐set enrichment analysis showed that the worsening of symptoms in early onset asthma correlated with lymphocyte activation, pathogen recognition, cytokine receptor activation, and lymphocyte differentiation. Conclusions Our findings suggest that early onset asthmareducedLF was the most genetically predisposed cluster, and that asthma clusters with reduced lung function were genetically distinct from clusters with normal lung function. Our study revealed the genetic variation between clusters that were segmented based on onset age and lung function, providing an important clue for the genetic mechanism of asthma heterogeneity.

Inorganic phosphate (Pi) is used extensively as a preservative and a flavor enhancer in the Western diet. As a result, dietary Pi intake in the US far exceeds the recommended daily allowance. A previous study from our laboratory has demonstrated that dietary Pi excess induces an exaggerated rise in blood pressure and renal sympathetic nerve activity (RSNA) in response to muscle contraction. This augmented pressor response was further shown to be mediated by an exaggerated skeletal muscle exercise pressor reflex (EPR). However, the underlying mechanism responsible for the EPR overactivity observed remains unknown. Fibroblast growth factor (FGF) 23 is one of the principle hormones involved in Pi homeostasis. It can cross the blood brain barrier and activate FGF receptors in the brainstem. The purpose of this study was to test the hypothesis that Pi‐induced EPR overactivity is mediated by brain FGF receptor stimulation. Sprague‐Dawley rats were fed a normal Pi (NP) diet containing 0.6% Pi (n=13) or a high Pi (HP) diet containing 1.2% Pi (n=13) for three months. Subsequently, mean arterial pressure (MAP) and RSNA responses to EPR activation were measured in decerebrate NP and HP animals. MAP and RSNA measures were obtained before and after intracerebroventricular (ICV) administration of the FGF receptor inhibitor PD173074. ICV PD173074 administration significantly reduced the exaggerated MAP (Δ=35±4 vs. 9±2 mmHg, P<0.01) and RSNA responses (Δ=84±16 vs. 32±7 %, P<0.01) to electrically induced hindlimb muscle contraction via ventral root stimulation (i.e. EPR activation) in the HP group, but did not significantly affect the responses in the NP group (ΔMAP =18±3 vs. 13±2 mmHg, ΔRSNA=40±10 vs. 30±7 %). MAP and RSNA responses to intra‐arterial infusion of capsaicin in the hindlimb (designed to assess the metabolically‐sensitive component of the EPR) were also attenuated by PD173074 in HP rats (ΔMAP=43±4 vs. 24±5 mmHg, ΔRSNA=98±25 vs. 48±9 %, P≤ 0.02) but remained unchanged in NP animals (ΔMAP=32±4 vs. 34±4 mmHg, ΔRSNA=61±12 vs. 66±18 %). The findings suggest that stimulation of FGF receptors in the brain contributes significantly to the generation of exaggerated EPR activity after excess Pi consumption. Moreover, the data demonstrate a novel action of central FGF receptor inhibition by reversing the EPR overactivity manifest in animals fed a high Pi diet. Importantly, the results implicate dietary Pi as a potential therapeutic target for the prevention and/or treatment of abnormally large sympathetic and blood pressure responses to exercise.Support or Funding InformationNIH 5RO1HL133179‐02This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

An increasing number of studies have reported a deleterious role of inorganic phosphate (Pi) in promoting hypertension. Previously, we have shown high Pi diet-induced excessive pressor and sympathetic responses to muscle contraction in otherwise normal rats, which were primarily mediated by an overactive exercise pressor reflex (EPR), a reflex arising from contracting muscle. However, the mechanism underlying these abnormalities generated by excess Pi intake remains unclear. Dietary Pi is known to increase release of bone-derived fibroblast growth factor (FGF) 23 to regulate Pi homeostasis. Evidence suggests that FGF23 and FGF receptors (FGFRs) are also present in the central nervous system. The aim of this study was to determine the role of brain FGFRs in mediating augmented EPR activity induced by dietary Pi excess. Accordingly, we assessed cerebrospinal fluid FGF23 levels in Sprague-Dawley rats fed either a normal 0.6% Pi diet (NP) or a high 1.2% Pi diet (HP) for 12 weeks. To determine the role of central FGFRs in mediating the EPR, we measured mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) responses to hindlimb muscle contraction before and after intracerebroventricular (ICV) administration of either a selective FGFR4 inhibitor BLU9931 or a FGFR1/2/3 inhibitor AZD4547 in decerebrate NP and HP animals. Cerebrospinal fluid FGF23 levels were significantly higher in HP rats compared to NP rats (8.3±0.9 vs. 7.2±0.8 pM, P<0.01). ICV BLU9931 injection markedly attenuated (all P<0.01) the heightened MAP (Δ=41±14 vs. 20±14 mmHg) and RSNA (Δ=112±70 vs. 65±46 %) responses to EPR activation in HP animals, but did not significantly affect the responses in NP animals (ΔMAP=11±3 vs. 7±4 mmHg, ΔRSNA=21±17 vs. 15±5 %). MAP and RSNA responses to EPR stimulation were unchanged by ICV AZD4547 administration in NP or HP rats. In conclusion, our data demonstrate a novel action of central FGFR4 inhibition by reducing the high Pi diet-mediated skeletal muscle reflex overactivation. Importantly, the results implicate that activation of brain FGFR4 may lead to sympathetic dysregulation contributing to the abnormal hypertensive responsiveness after excess Pi consumption.

Stimulation of the mesencephalic locomotor region (a putative component of the central command pathway) has been shown to elicit exaggerated pressor and sympathetic nerve responses in decerebrate spontaneously hypertensive rats (SHR) as compared to normotensive Wister‐Kyoto rats. This finding suggests that central command activity and/or influence on caudal vasomotor centers may be augmented in hypertension. In the normotensive decerebrate rat model, mean arterial pressure (MAP) and sympathetic nerve activity are known to increase during intermittent bouts of spontaneous motor activity. Moreover, evidence suggests that simulated central command influences at the brainstem may evoke these pressor and sympathetic responses. However, it remains unknown whether these spontaneous changes in cardiovascular hemodynamics are altered with the pathogenesis of hypertension. Based on this background, we hypothesized that the pressor and sympathetic nerve responses during spontaneously‐occurring motor activity are exaggerated in hypertension. MAP, renal sympathetic nerve activity (RSNA), and tibial nerve discharge were measured in decerebrate SHR (n=8) and normotensive Sprague‐Dawley (SD) rats (n=6). The present study aimed to compare resting baroreflex changes in RSNA (in response to pharmacological alterations in MAP) and central command‐evoked responses in MAP and RSNA during spontaneously‐occurring motor activity between SHR and normotensive SD. Results demonstrated that the baroreflex‐mediated RSNA response was not different between SHR and SD. In both SHR and SD, abrupt, spontaneous increases in RSNA were synchronized with tibial motor discharge and followed by a rise in MAP. These potentially central command‐evoked increases in MAP and RSNA were greater in SHR than SD. Phenylephrine‐induced elevations in MAP did not suppress the central command‐induced RSNA increase in SHR, whereas it abolished the rise in RSNA in SD. Taken together, it is concluded that 1) the arterial baroreflex is operative during resting conditions in SHR as well as SD; 2) the pressor and sympathetic nerve responses during spontaneously‐occurring motor activity are exaggerated in hypertensive rats; and 3) exaggerated RSNA responses in SHR may be induced along a central command pathway independent of the arterial baroreflex and/or as a result of central command‐induced inhibition of the arterial baroreflex itself.

High‐intensity interval training (HIIT) on the treadmill has been reported to be more effective in improving aerobic fitness and cardiac function compared with moderate‐intensity continuous training (MICT) in adults with cardiometabolic disorders. However, middle‐aged and older adults with type 2 diabetes (T2D) are often unable to tolerate weight‐bearing exercise which may hinder HIIT and MICT on the treadmill. Therefore, the purpose of this randomized clinical trial was twofold: 1) to test if non‐weight bearing all‐extremity HIIT and MICT are feasible in adults with T2D aged 50 to 79 yrs; and 2) to test whether HIIT is more effective in improving aerobic fitness and cardiac function than MICT. Fifty‐three sedentary adults with T2D (age: 63±1 yrs), free of cardiovascular disease, were randomized to HIIT (n=21), MICT (n=18) or non‐exercise control (CONT; n=14). HIIT (4×4‐min intervals at 90% of peak heart rate; HRpeak) and isocaloric MICT (70% of HRpeak) were performed on an all‐extremity ergometer, 4 times/week for 8 weeks under supervision. Aerobic fitness was assessed by oxygen consumption during an incremental maximal exercise test. Left ventricular (LV) function was assessed during rest by two‐dimensional echocardiography including conventional and tissue Doppler. All measures were obtained at pre‐ and post‐intervention. Approximately 80% of participants randomized to all‐extremity HIIT and MICT completed the exercise intervention. Aerobic fitness improved by 11% in HIIT (22.4±1.2 vs. 24.9±1.4 ml/kg/min, pre‐ vs. post‐intervention; P<0.0001) and 7% in MICT (21.4±1.3 vs. 23.0±1.3 ml/kg/min; P=0.004 and P=0.4 for HIIT vs. MICT), whereas it did not change in CONT (21.4±1.5 vs. 21.3±1.2 ml/kg/min; P=0.9). Ejection fraction, a measure of LV systolic function, increased in both HIIT and MICT by ~2% (HIIT: 54.7±0.7 vs. 56.6±0.9%; P=0.007 and MICT: 54.6±1.4 vs. 56.4±1.2%; P=0.04), whereas it remained unchanged in CONT (56.0±1.2 vs. 54.9±1.1%; P=0.2). Diastolic function was not significantly affected by the intervention (P≥0.06). In conclusion, all‐extremity HIIT and MICT are feasible in middle‐aged and older adults with T2D and are equally effective in improving aerobic fitness and LV systolic function.Support or Funding InformationThis work was supported by the National Institutes of Health (NIA AG 050203).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.